The statements in this section merely provide background information related to the present disclosure and may not constitute prior art.
The T-cell receptor (TCR) is composed of at least 7 integral membrane proteins. On a majority of peripheral T-cells the TCR contains a clonally distributed disulphide linked hetero-dimer consisting of an α TCR chain and αβ TCR chain. These clonotypic chains are subdivided into variable (V), joining (J) and constant (C) segments for the α chain and a Diversity (D) segment for the β chain. Associated with the αβ TCR are three invariant chains that form the CD3 complex. The αβ TCR is critical for antigen/MHC recognition while the CD3 proteins play an important role in signal transduction.
The structure of the αβ TCR chains is similar to that of antibodies, with the variable regions resulting from genetic recombination, generating the large diversity of TCR repertoires. On the other hand, the constant and transmembrane regions of the αβ TCR are conserved. These conserved regions are very important, as they play a role in the binding of the α and β chains, interact with the CD3 proteins, and play a role in the transport of TCR components from the endoplasmic reticulum to the cell surface. Patients who have mutations within the constant region may have a poorly functioning αβ TCR, but more commonly fail to express a TCR at all. Physiologically, patients with these mutations suffer from severe immunodeficiency. One recent study in the Journal of Clinical investigation showed in multiple patients that a genetic impairment at the last base of exon 3 immediately following the translational termination codon in the α TCR subunit constant gene resulted in severe immunodeficiency in infants, requiring lifelong antiviral and antibiotic prophylaxis (Morgan, et al., “Mutation in the TCRα subunit constant gene (TRAC) leads to a human immunodeficiency disorder characterized by a lack of TCRαβ+ T-cells”. J. Clin. Invest., February 2011).
In the absence of immunosuppressive intervention following allogeneic solid organ transplantation, donor and recipient antigen-presenting cells present graft antigens to alloreactive alpha-beta (αβ) T-cells, which, when activated, result in an inflammatory response and rapid rejection of the allograft. These T-cells, which include T-helper (CD4) and cytotoxic (CD8) T-cells, are critical in the acute organ transplant rejection response since they recognize allogeneic antigens, including major histocompatibility complex (MHC) antigens, as foreign, Gamma-delta (γδ) T-cells express the γδ T-cell receptor (TCR) and generally do not recognize protein antigens in the context of MHC but rather recognize unconventional, non-protein antigens. γδ T-cells may be of benefit to renal transplant patients from several perspectives, including providing protection against a variety of microbial infections to which immune suppressed transplant patients are particularly vulnerable. Such infections include cytomegalovirus (CMV), a common viral infection in transplant patients that, through its immunosuppressive properties, can lead to other opportunistic infections as well as post-transplant lymphoproliferative disorders.
In mice and in humans, the presence of donor γδ T-cells is associated with better outcomes in bone marrow transplant models, in part through prevention of graft-versus-host disease (GVHD), though the mechanisms are not fully understood. One subset of γδ T-cells is a rare population in the peripheral blood of normal humans and the majority of liver transplant patients, but expands to a higher frequency compared to other γδ T-cell subsets in the peripheral blood of “operationally tolerant” liver transplant patients. These patients are considered “operationally tolerant” because they have achieved a level of tolerance to the allograft that allows total removal from immunosuppression. This expanded subset of γδ T-cells is the same one that is associated with tolerance to semi-allogeneic antigens in pregnant individuals, indicating that these cells may have an important role in the generation and/or maintenance of tolerance against allogeneic antigens. In addition, a reduction in peripheral γδ T-cells is associated with acute and chronic renal allograft rejection, while stable, non-rejecting kidney transplant patients have a higher percentage of γδ T-cells, on average. Together, these studies indicate that an immunosuppressive agent that spares depletion or inactivation of γδ T-cells may be associated with better outcomes.
An unmet medical need exists for an agent capable of selectively inactivating specific αβ T-cells in a non-mitogenic manner, without unnecessarily exposing the patient to non-specific, long term, or open-ended immune suppression, which may exacerbate the risks of infections and malignancies. Gamma-delta T-cells are important mediators in the protection against infectious agents and share several features in common with αβ T-cells, including the expression of CD25, CD52 and CD3. As such, currently used induction therapies, including Anti-thymocyte globulin (ATG), alemtuzumab, basiliximab and daclizumab, target not only alto-reactive T-cells but also γδ T-cells and NK cells. A more specific approach to prevention of acute organ rejection or to treat inflammatory or autoimmune diseases by targeting the αβ TCR alone, sparing γδ T-cells, may provide similar or better efficacy than the currently used T-cell targeting antibodies while carrying fewer risks in terms of development of opportunistic infections and malignancies. Although the development of some αβ TCR-specific antibodies has been attempted, none have exhibited both sufficient clinical efficacy and an acceptable safety profile. There is therefore a need for αβ TCR-specific antibodies that exhibit efficacy in diseases and conditions including inflammatory diseases, autoimmune diseases, and allograft rejection, while exhibiting minimal adverse effects.